1. Field of the Invention
This invention relates to particular aldoxime salts useful in the treatment of poisoning by certain chemicals containing phosphorus. More particularly, this invention relates to particular classes of substituted imidazolium-2-aldoxime salts.
2. Description of the Related Art
Certain organic chemicals containing phosphorus including some agriculture chemicals (pesticides) such as parathion, chemical warfare agents such as Soman and Tabun, and other organo-phosphorus chemicals such as ethyl-p-nitrophenyl methylphosphonate (EPMP) attack the central nervous system of animals, including humans, and inactivate the body's naturally produced enzyme acetylcholinesterase, sometimes also called cholinesterase. This enzyme is used in living organisms to break down the naturally produced acetylcholine released by cholinergic neurons as a part of normal function of the autonomic nervous system.
Administration of the drug atropine has long been used as a treatment for the effects of such poisoning. For example, it increases the heart rate which would otherwise be decreased by an excess of acetylcholine in the system due to inactivation of the acetylcholinesterase enzyme which normally would immediately break down the acetylcholine. However, atropine cannot restore activity to (reactivate) the inhibited acetylcholinesterase. Other drugs, therefore, are conventionally administered with atropine to reactivate the acetylcholinesterase enzyme. Such drugs include toxogonin and 2-PAM, which contains the active agent 2-(hydroxyimino)methyl-1-methylpyridinium chloride.
Hagedorn U.S. Pat. Nos. 3,773,775 and 3,852,294 describe the use of (hydroxyimino)methylpyridinium compounds for treating and alleviating the symptoms of poisoning caused by exposure to phosphorus containing pesticides and war gases.
Poziomek et al., in an article entitled "Pyridinium aldoximes" published in the Journal of Organic Chemistry, Vol. 23 in 1958 at pp. 714-717, describe the preparation and testing of a number of pyridinium aldo ximes including 1,1'-polymethylenebis(4-formylpyridinium bromide) dioximes and N-substituted 2- and 4-formylpyridinium halide oximes and report that the bis-quaternary dioximes are active as chemotherapeutic agents in the treatment of acetylcholinesterase poisoning in experimental animals.
Wilson et al., in "A Specific Antidote Against Lethal Alkyl Phosphate Intoxification. V. Antidotal Properties", published in the Archives of Biochemistry and Biophysics, Vol. 69, in 1957 at pp. 468-474, discusses the effects of pyridine-2-aldoxime methiodide as an in vitro reactivator of alkyl phosphate-inhibited acetylcholinesterase.
However, these pyridine-based chemical agents are not always effective in reactivating the acetylcholinesterase enzyme, particularly when the body has been exposed to a large dosage of the acetylcholinesterase enzyme-inactivating chemical. Furthermore, the synthesis of at least some pyridine-based compounds requires the use of the known carcinogen bis-chloromethyl ether and a major requirement in the use of these oxime therapeutics is to guarantee to the Food and Drug Administration (FDA) in IND and NDA reports that no carcinogenic materials remain in the final product.
It was also found that attempts to produce some oxime-substituted pyridine-based chemicals resulted in the formation of derivatives which were relatively unstable and could not, therefore, be stored very long, which made their potential use as therapeutic agents dubious at best.
It is known that alkylimidazoles have therapeutic effects as treatment agents. Wilkinson et al., in "Structure-Activity Relationships in The Effects Of 1-alkylimidazoles On Microsomal Oxidation In Vitro And In Vivo", published in the Journal of Biochemical Pharmacology, Vol. 23 in 1974 at pp. 2377-2386, describes the biological activities of a number of 1-alkyl substituted imidazole compounds including activity as inhibitors of drug oxidation and potentiators of barbituate sleeping time in mammals.
Iversen et al., in an article entitled "Preparation of 2-Imidazole and 2-Thiazolecarbaldehydes", published in ACTA Chem. Scand., Vol. 20, No. 10, in 1966, at pp. 2649-2657, report the preparation of a series of 2-imidazole- and 2-thioazolecarbaldehydes from imidazole and thiazole with the carbaldehyde in the 2-position.
The use of (hydroxyimino)methylimidazoles (aldoxime-substituted azolium derivatives) has also been explored by others for the treatment of organophosphorus poisoning in comparison to the pyridine-based 2-PAM standard treatment agent. Grifantini et al., in an article entitled "Structure-Activity Relationships in Reactivators of Organophosphorus-Inhibited Acetylcholinesterase V: Quaternary Salts of Hydroxyiminomethylim:idazoles", published in the Journal of Pharmaceutical Sciences, vol. 64, No. 4, in 1972 at pp. 631-633, describes the effectiveness of quaternary salts of some derivatives of 2-(hydroxyimino)methylimidazole and 5-(hydroxyimino)methylimidazole on the reactivation of organophosphorus-inhibited acetylcholinesterase when inhibited by diethylphosphoryl and diisopropylphosphoryl groups. The reactivities of the two 2-(hydroxyimino)methylimidazole derivatives tested were respectively reported as a half and a fourth of that of 2-(hydroxyimino)methyl-l-methylpyridinium iodide (2-PAM).
Herrador et al., in an article entitled "Reactivators of Organophosphorus-Inhibited Acetylcholinesterase. 1. Imidazole Oxime Derivatives", published in the Journal of Medicinal Chemistry, Vol 28, in 1985 at pp. 146-149, discloses the synthesis and biological screening of 1-aryl(alkyl)-4-[(hydroxyimino)-methyl]-3-methylimidazolium iodides and 1-aryl(alkyl)-4-[(hydroxyimino)methyl]-3-methyl-2-(methylthio)-imidazolium iodides as potential reactivators of organophosphorus-inhibited acetylcholinesterase. All materials tested were reported as weak reactivators with the best ones said to be about two times less active than 2-PAM.
Bedford et al., in an article entitled "Structure-Activity Relationships for Reactivators of Organophosphorus-Inhibited Acetylcholinesterase: Quaternary Salts of 2-[(Hydroxyimino)methyl]imidazole" coauthored by some of us and published in the Journal of Medicinal Chemistry, Vol. 27, No. 11, 1984, at pages 1431-1438, discussed the in vitro testing of 1-methyl-2-(hydroxyimino)methyl-3-(alkoxy or aralkoxy)methyl-imidazolium chloride salts as reactivators of eel acetylcholinesterase inhibited by 3,3-dimethyl-2-butyl methylphosphonofluoridate (GD or Soman).
While the 2-[(hydroxyimino)methyl]imidazolium salts reported in this article have been subsequently found to be sufficiently effective in the treatment of acetylcholinesterase inhibited by organo-phosphorus compounds to save as high as 60% of mice injected with a lethal dose (LD.sub.50) of Soman, it has also been found that the toxicity of such compounds is also quite high as determined by the low value of the LD.sub.50 of the antidotal compound, i.e., the lower the amount of the antidotal compound which is lethal to 50% of the species to which it is administered, the more toxic the compound. When the antidotal compound has a low LD50, less of it can be safely administered to the species as an antidote to the organo-phosphoric chemical
It, therefore, would be beneficial to provide a class of low toxicity, stable aldoxime-substituted imidazolium derivatives which would be more effective than standard pyridine-based treatment agents such as 2-PAM in the reactivation of the acetylcholinesterase enzyme and which would be capable of being produced without the use of precursors which are known carcinogens Surprisingly, despite the teachings of the prior art, we have discovered a class of stable aldoxime-substituted imidazolium derivatives which are more effective than 2-PAM in the reactivation of acetylcholinesterase and yet have low toxicity.